Aminoalkylsterol compounds with antitumoral and neuroprotective activity

Abstract

Sterol derivatives of formula (I) and a method for the production of the compounds, a medicament using one of the compounds and a pharmaceutical composition comprising the medicament.

The invention claimed is: 
     
       1. A sterol-based compound, corresponding to formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         T 1  and T 2  represent, independently, H or CH 3  with CH 3  in the α and/or β position; 
         T 4  represents H, CH 3  or C 2 H 5 ; 
         T 3  represents H or a β CH 3 ; 
         the bond between carbons 5 and 6 is a single bond and the bond between carbons 7 and 8 is a single or a double bond; 
         Z is in position 5 and represents OH; and 
         R is in position 6 or 7, on a carbon not bearing a double bond, and represents a substituent of formula -Q 0 -Q 1  wherein: 
         -Q 0 - represents the radical of formula (II):
   —X—(CH 2 ) no [Y 1 —(CH 2 ) n1 ] p1 [Y 2 —(CH 2 ) n2 ] p2 [Y 3 —(CH 2 ) n3 ] p3 [Y 4 —(CH 2 ) n4 ] p4 [Y 5 —(CH 2 ) n5 ] p5 —  (II)
 
 
       
       in which formula (II):
 p1, p2, p3, p4 and p5 are integers independently equal to 0 or 1, 
 n0, n1, n2, n3, n4 and n5 are independent integers such that:
   1 ≦n 0≦4
 
   0 ≦n 1 ,n 2 ,n 3 ,n 4 ,n 5≦4
 
 
 —X— represents —S—, —O—, —CH 2 —, —NR 3 —, in which R 3  is H or a C 1 -C 4  alkyl radical, or a heterocycle 
 
       
         
           
           
               
               
           
         
         —Y 1 —, —Y 2 —, —Y 3 —, —Y 4 — and —Y 5 — represent, independently of each other, —S—, —O—, —CH 2 — or —NR 3 —, in which R 3  has the meaning given above; 
         -Q 1  represents an indole nucleus, a morpholine or thiomorpholine nucleus attached via its nitrogen atom, a heterocycle 
       
       
         
           
           
               
               
           
         
       
       in which R 1  represents H, COCH 3 , or a C 1 -C 4  alkyl radical, or Q 1  represents 
       
         
           
           
               
               
           
         
       
       in which R 1  has the meanings given above and R 2  represents H or a C 1 -C 4  alkyl radical, or R 1  and R 2  together constitute a piperidine, pyridine or piperazine ring optionally substituted with a C 2 -C 4  alkyl radical, or constitute a pyrrole or pyrrolidine heterocycle comprising a nitrogen atom and 4 carbon atoms, with the proviso that:
 if —X-=—NH— and 
 
       
         
           
           
               
               
           
         
          at least one of the numbers p1, p2, p3, p4 and p5 is other than 0; and 
         if —X—=—CH 2 —, n0=1 and all the numbers p1, p2, p3, p4 and p5 are zero, Q 2  is other than —NH 2 . 
       
     
     
       2. The sterol-based compound of formula (I) as claimed in  claim 1  wherein:
 R is in position 6 and represents the substituent of formula -Q 0 Q 1  as defined in  claim 1 . 
 
     
     
       3. The sterol-based compound of formula (I) as claimed in  claim 1 , wherein the bond between carbons C 7  and C 8  is a double bond, R═NH—(CH 2 ) 3 —NH—(CH 2 ) 4 —NH 2  and T 2 =T 2 =T 3 =H. 
     
     
       4. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond between carbons C 7  and C 8  is a double bond, T 2 =T 2 =T 3 =H and R═NH—(CH 2 ) 3 —NH—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH 2 . 
     
     
       5. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond between carbons C 7  and C 8  is a double bond, T 2 =T 2 =T 3 =H and 
       
         
           
           
               
               
           
         
       
     
     
       6. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond between carbons C 7  and C 8  is a double bond, T 2 =T 2 =T 3 =H and R═—H—(CH 2 ) 4 —NH 2 . 
     
     
       7. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond C 7 -C 8  is a double bond, T 2 =T 2 =T 3 =H and R═—NH—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH 2 . 
     
     
       8. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond C 7 -C 8  is a single bond, T 2 =T 2 =T 3 =H and R is in position 6 and R═—NH—(CH 2 ) 3 —NH—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH 2 . 
     
     
       9. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond C 7 -C 8  is a single bond, T 2 =T 2 =T 3 =H and R is in position 6 and represents: 
       
         
           
           
               
               
           
         
       
     
     
       10. The sterol-based compound of formula (I) as claimed in  claim 1  wherein the bond C 7 -C 8  is a single bond, T 2 =T 2 =T 3 =H and R is in position 6 and represents R═NH—(CH 2 ) 3 —NH—(CH 2 ) 4 —NH 2 . 
     
     
       11. The sterol-based compound of formula (I) as claimed in  claim 1  selected from the group consisting of:
 cholestane-3β, 5α diol-6β-N-[1-N1-(3-aminopropyl)butane-1,4-diamine]; 
 cholest-7-ene-3β, 5α diol-6β-N-[1-N-1-(3-aminopropyl)butane-1,4-diamine]; 
 cholest-7-ene-3β, 5α diol-6β-N-[2-ethylamino-(1H-imidazol-4-yl)]; 
 cholestane-3β, 5α diol-6β-N-[2-ethylamino(1H-imidazol-4-yl)]; 
 cholest-7-ene-3β, 5α diol-6β-N-(4-aminobutylamine); 
 cholest-7-ene-3β, 5α diol-6β-N-{2-[2-(2-amino-ethoxy)ethoxy]ethylamine}; 
 cholestane-3β, 5α diol-6β-(3-aminopropylamine); 
 cholestane-3β, 5α diol-6β-(4-aminobutylamine); 
 cholestane-3β, 5α diol-6β-(6-aminohexylamine); 
 cholestene-7-3β, 5α diol-6β-(3-aminopropylamine); 
 cholestene-7-3β, 5α diol-6β-(6-aminohexylamine); 
 cholestane-3β, 5α diol-6β-{[2-(1H-imidazol-4-yl)ethyl]methylamine}; 
 cholest-7-ene-3β, 5α diol-6β-{[2-(1H-imidazol-4-yl)ethyl]methylamine}; 
 sitostane-3β, 5α diol-6β-(3-aminopropylamine); 
 sitostane-3β,5α diol-6β-(4-aminobutylamine); 
 campestane-3β, 5α diol-6β-(3-aminopropylamine); 
 campestane-3β, 5α diol-6β-(4-aminopropylamine); 
 sitostane-3β, 5α diol-6β-(6-aminohexylamine); 
 campestane-3β, 5α diol-6β-(6-aminohexylamine); 
 sitostane-3β, 5α diol-6β-N-[1-N1-(3-aminopropyl)butane-1,4-diamine]; 
 campestane-3β, 5α diol-6β-N-[1-N-1-(3-aminopropyl)butane-1,4-diamine]; 
 sitostane-3β, 5α diol-6β-N-{[2-(1H-imidazol-4-yl)ethyl]ethylamine}; and 
 campestane-3β, 5α diol-6β-N-{[2-(1H-imidazol-4-yl)ethyl]ethylamine}. 
 
     
     
       12. A process for preparing a sterol-based compound of formula (I) as claimed in  claim 1 , comprising:
 in a first step, reacting meta-chloroperoxybenzoic acid, dissolved in methylene chloride, with a compound corresponding to formula (III), said compound being dissolved in a solvent selected from the group consisting of methylene chloride, a mixture of methylene chloride with water and a mixture of methyle chloride and aqueous Na 2 CO 3  solution, 
 
       
         
           
           
               
               
           
         
         wherein: 
         T 1  and T 2  are, independently, H or CH 3  with CH 3  in the α and/or β position, 
         T 4  represents H, CH 3  or C 2 H 5 , 
         T 3  represents H or a β CH 3 , 
         the bond between carbons 5 and 6 is a single bond, and the bond between carbons 7 and 8 is a single or a double bond; and 
         in a second step, reacting the epoxy compound obtained in the first step, dissolved in a solvent selected from the group consisting of an ethanolic solution, anhydrous ethanol and pyridine in the presence of lithium perchlorate, with an amine of formula HQ 0 Q 1 , wherein Q 0  and Q 1  are as defined in  claim 1 . 
       
     
     
       13. The process as claimed in  claim 12 , wherein the product obtained in the first step is purified before using it for the second step. 
     
     
       14. The process as claimed in  claim 12 , wherein the reaction of the second step is performed at reflux and under atmospheric pressure. 
     
     
       15. A medicament comprising at least one compound as claimed in  claim 1  in association with a pharmaceutically acceptable vehicle. 
     
     
       16. A sterol-based compound corresponding to formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 (i) T 4  represents CH 3  or C 2 H 5 ; and 
 
         the bond C 7 -C 8  is a single bond, Z represents OH in position 5, T 1 =T 2 =T 3 =H, and R is in position 6 and represents: 
       
       
         
           
           
               
               
           
         
         or
 (ii) T 4  represents H, CH 3  or C 2 H 5 ; and 
 
         the bond C 7 -C 8  is a single bond, Z represents OH in position 5, T 1 =T 2 =T 3 =H, and R is in position 6 and represents: 
       
       
         
           
           
               
               
           
         
       
     
     
       17. The sterol-based compound of formula (I) according to  claim 16 , which is cholestane-3β,5α diol-6β-N-({1H-imidazol-4-yl}ethyl)acetamide. 
     
     
       18. A sterol-based compound selected from the group consisting of:
 cholestane-3β,5α diol-6β-N—[N,N′-bis(3-aminopropyl)butane-1,4-diamine]; 
 cholest-7-ene-3β,5α diol-6β-N—[N,N′-bis(3-aminopropyl)butane-1,4-diamine]; 
 cholestane-3β,5α diol-6β-N-({1H-imidazol-4-yl}ethyl)acetamide; 
 cholestane-3β,5α diol-6β-(3-aminopropylacetamide); 
 cholestane-3β,5α diol-6β-(4-aminobutylyl-1-acetamide); 
 cholestane-3β,5α-diol-6β-(6-aminohexylacetamide); 
 cholestene-7-3β,5α diol-6β-(3-aminopropylacetamide); 
 cholest-7-ene-3β,5α diol-6β-(4-aminobutylyl-1-acetamide); 
 cholestene-7-3β,5α diol-6β-(6-aminohexylacetamide); 
 sitostane-3β,5α diol-6β-(3-aminopropylacetamide); 
 campestane-3β,5α diol-6β-(3-aminopropylacetamide); 
 campestane-3β,5α diol-6β-(4-aminobutyl-1-acetamide); 
 sitostane-3β,5α diol-6β-(6-aminohexylacetamide); 
 campestane-3β,5α diol-6β-(6-aminohexylacetamide); 
 sitostane-3β,5α diol-6β-N—[N,N′-bis(aminopropyl)butane-1,4-diamine]; and 
 campestane-3β,5α diol-6β-N—[N,N′-bis(aminopropyl)butane-1,4-diamine].